Every time I try to write, I have very good points and important things to say, but my body always feels otherwise and manages to erase everything I took hours to write. And it’s too difficult and time-consuming to redo everything since most of it was a kind of stream of consciousness endeavor. It’s tragic and very sad because my thoughts., I believe , are important in the conversation, and especially germane to this subject
That happens a lot to me too! 🤕 So I don't compose comments in Substack, as it doesn't save as I write. I write instead in Gmail or Google Docs, which automatically save. Then I copy and paste it into Substack. That might be worth a try? There are lots of apps that save as one writers, Word can if one sets it to do that. I back everything up to Google Drive. There are phone based apps one can use also. Perhaps find the one that is easiest for you to use 👍
I understand many of these issues, and the vital importance of empirical research. But it also takes quite a bit of time, and many of us pwMS don’t have years and years of time to wait for clinical trials to play out. This is not a complaint, it’s just a fact. I was Dx'd (diagnosed) with multiple sclerosis in 2002, and I was originally hopeful that science and technology in the new millennium would have concrete answers quite soo. But after
Unfortunately, Science moves very slowly. We put forward the alemtuzumab-rituximab hypothesis in 2014. If we had been funded I suspect we would have had the results by now. Saying that we can't simply adopt a treatment protocol, particularly an expensive and potentially risky one, without more evidence in the NHS. There are checks and balances in the NHS, which makes it very hard to prescribe off-label. I suspect it will be easier in the private sector.
I was hopeful that this time in history medical science would be able to catch up to the disease, as the disease had a 167 year head start. But for the last 20+ years the people charged with developing the therapies (aka the drug companies, etc ) decided to become intransigently insular, and only come at the disease with a linear progression of similar products… as if they were catering to a MultipleSclerosis department store. We (pwMS) need more rigorous work done on figuring out how the disease works on a fundamental level, how to arrest the progression at the molecular level, and how to repair the damage if it’s possible. We don’t need more ridiculously varied alternative brands of CD 20 inhibitors, or another -imod or BTK inhibitor. It’s the waste of precious time that I’m talking about, not that the wheels of science turn slowly.
I understand about having to run clinical trials to be able to make sure that a therapy is safe and efficacious. But to be frank, we don’t have time anymore for people to fart around with science just trying to monetarily ingratiate their stockholders. I am painfully aware how cynical that sounds, but I’ve learned to be more skeptical after all that I’ve experienced in the past 20 years dealing with multiple doctors and drug companies. I was in school in 2004 and trying to transfer to a four-year university here near me. I knew a professor (Prof Peter Bryant) at the University of California Irvine for years, because my mother worked as a secretary for the dean of the pathobiology department (now known as the molecular biology department), and he was trying to help me fast track into the university. In the meantime, I was assisting in his stem cell lab at the university. At one point there was a symposium put on by the university and the then newly established CIRM (California Institute for Regenerative Medicine), and I had pretty extensive conversations with some of the scientists. I asked about being able to repair damage from multiple sclerosis with stem cells, and was told that it was a possibility someday, but that the science was still 40 to 50 years away from being able to do that, period, let alone effectively. That had a huge impact on my hopes of what was possible. I never was able to transfer to the university because the disease caught up to me exponentially, and I had to drop out of school before the disability caused so much disruption that my GPA bottomed out completely. It’s unfortunate because I really thrived in that environment.
Just a sidenote… but UCI was the home of Dr Stanley van den Noort, and I actually got a chance to meet him once before he passed away. Though he had given up his practice by then.
Quite a lot (trials / studies) going on in the MS research world - rituximab after Alemtuzumab, BTK inhibitors, Frexalimab, Sizomus, Chariot MS, Octopus, Cambridge remyelination trial…. But nothing from these trials / projects (if positive) will be available for another 5+ years. It’s like being in a desert desperate for water. A mirage appears, but as soon as you get close it moves away. Is there nothing else likely to emerge in a a shorter timeframe? What happened to the Black Swan? Why does the U.K. appear to be doing all the donkey work?
Not sure it is a mirage. When you look back at the development history of most MS treatments they take decades from concept to a licensed treatment. Sadly, this is the nature of science and drug development.
MS research has kept teams of scientists busy for decades and anti-relapse drugs have been a cash cow for pharma. Compared to research re AIDS, Covid and many cancers, MS research has been in the slow lane for too long. The case below brings tears to my eyes, but highlights the importance of breaking the current models of working which have delivered too many failures (eg anti-lingo antibody, drugs to slow / stop progression) and taken too long.
Some of your colleagues acknowledge that the main progress has been anti-relapse (not the real disease) drugs and the big questions have still to be answered:
I had my second course of Alemtuzumab last October at Royal London. Honestly, it was fine, just far, far too late; I was extremely glad to have it. So far, I haven't developed any new conditions from it, though my lymphocyte count isn't yet back to anywhere near a normal level. I'm interested in the idea of taking other treatments alongside Alumtuzumab, and would have been willing to be in a trial (and would still be willing, if I have more treatment, which I'm trying to just keep an open mind about.)
Jun 5, 2023·edited Jun 5, 2023Liked by Gavin Giovannoni
This is fascinating academic debate that never seems to mention the patients. We are the ones who have to experience/suffer/endure/be treated for these complications, often for the rest of our lives. Whilst the benefits of alemtuzumab for MS outweigh - for most of us - these risks then taking the drug isn't the issue here.
As these risks after a course of alemtuzumab treatment are well known and in many cases quite quantifiable (Graves for example) to just put them all to one side because there is insufficient Placebo Controlled, Randomised, Clinical Trial evidence at present seems to skirt past the growing body of Real World Evidence. RWE is not a fanciful notion and can be derived from observation.
For example: the Whack-A-Mole trial referred to may only have had 10 participants making it woefully underpowered it is my understanding that c. 400 patients have been treated with this protocol or variations thereof. Apparently, not a single person has had any auto-immune issues related to their alemtuzumab infusion. Acknowledging that there are uncontrollable variables and this is NOT hard scientific method data it makes one wonder why there hasn't been a single incidence. In a cohort of c. 400 there would be an expectation of - taking Graves as an example - at least 1/3 having thyroid issues. Roughly, granted. But not one.
The protocol, in whatever form, was not administered by have-a-go amateurs but by specialist neurologists using drugs that have well-established safety profiles. The question of on or off-license use is a confounding factor in differing countries but should not be used to cloud the discussion about whether this expert-led attempts at 'painting outside the lines' works or not.
Until alemtuzumab regains its popularity as a go-to medicine for MS then there will be relatively little commercial interest in mitigating risks. The academic speculating discussed here has the feeling of an existential debate about the hardest science possible, not the end users.
In the meantime, there are actual people, MS patients, who are going to receive alemtuzumab who I imagine are more than willing to try something to mitigate risks. After all, they already have MS and any of the compounds discussed here are not experimental drugs.
I also understand that a lot of tweaking/playing around etc has been done by various neurologists regarding the pre and post infusion regimes of various steroids, antibiotics, and antivirals all with the aim of reducing reactions to alemtuzumab. It would be interesting to see them collated, compared, and remarked upon by an expert such as yourself.
This is actually about mitigating the long term risks to the alemtuzumab recipients using best efforts. They may not be perfect, they may not be proven beyond a shadow of doubt, they may involve using a known compound off-license (hardly a new thing for medicine when a drug for X has been observed to do Y. Think Viagra, Rogaine, Tecfidera - all eventually re-trialled but used off label initially for their effects on another condition than the initial intended indication) all in an imperfect attempt to reduce the long-term negative effects of something.
Preserving an approach in aspic has rarely been a useful approach. Innovation and discovery has often been achieved by people wishing to push boundaries. RCT is the gold standard but in the meantime the issues don't go away and there is a degree of reputable evidence. Even you had the hypothesis initially!
I agree a lot of repurposing does result from off-label use, which then sets the scene for future randomised controlled trials. One could argue that this has already happened with the alemtuzumab-rituximab whack-a-mole paper and the Australians have risen to the challenge.
It is important to note that once the alemtuzumab clinical trial programme got underway Cambridge stopped dosing off-label CAMPATH-1H for compassionate use. They had lost equipoise and they told patients that they would have to wait for the randomised trials to report out.
NHS England would potentially respond to RWE, but it will need to be in a peer-review publication and of sufficient quality for them to accept it. And possibly from multiple sources. Let's hope someone publishes it soon; a 100% success rate would make a very compelling case.
I was told this by a very reputable source in Canada/US. Whilst I have no reason to doubt them I wouldn't bet anything significant on it because, as you say, it isn't in a paper. It seems that this is them and a colleague doing a tally and coming up with a reasonable number. I tried to phrase the fact that it is reportage carefully.
Hi Gavin, it's Elliot Frohman. Thanks for your comments as always.
I hope you are well. We missed having you at the MS Section of the AAN Chair's INTL Advisory Roundtable. Perhaps another time. You'll be very pleased to know that Tree and I are in discussion with a major benefactor concerning the funding of a randomized, prospective, controlled trial of the Teresa Frohman Whack-A-Mole protocol. Very excited about this, and agree it should be done. At one point we tried to invite you to join us, but never heard back. Best always, Elliot and Tree
Elliot, Do you have more anecdotal evidence than what you presented in your whack-a-mole paper? Some people seem to think there are now 100s of patients who have been treated with your protocol. Thanks.
Too many emails and not enough minutes or hours in a day. Apologies. Looks like the Australians have beaten you to the trial. But may be you can do one when you start rituximab earlier than 10 weeks post alemtuzumab. I would suggest W4 after the acute infection risk is waning.
Thank you for writing this - this topic interests me greatly so I’m always watching for your opinion. I wish very much I could try this process but understand the requirements of research practice. I hope the results are favourable & it’s not too late for me to benefit! :)
I'm still hung up on the palifermin behaving the opposite way they expected it to with dramatic negative consequences. Did they give these vulnerable people the first in human palifermin infusions? Yikes.
having since actually done my research (hah!) I see that it's long been used in a population where it might be hard to detect reduced thymopoesis. But still! It's weird to me to use a drug that has been used in humans on the strength of its use in nhps.
Good morning, just to add a comment on a secondary autoimmunity, in my case after HSCT. I just got a positive result for anti-NMDA-NR1-Receptor. The result was negative prior to HSCT and the bref EBV activation that had followed HSCT. Wondering if it could be a case of a secondary autoimmunity...will follow-up with doctors here.
I got a rituximab infusion at the end of my HSCT treatment - what is the role of it in this case? I am ignorant to the medicine/science in this respect. Is it a similar idea to prevent secondary autoimmunity after the chemo?
Every time I try to write, I have very good points and important things to say, but my body always feels otherwise and manages to erase everything I took hours to write. And it’s too difficult and time-consuming to redo everything since most of it was a kind of stream of consciousness endeavor. It’s tragic and very sad because my thoughts., I believe , are important in the conversation, and especially germane to this subject
That happens a lot to me too! 🤕 So I don't compose comments in Substack, as it doesn't save as I write. I write instead in Gmail or Google Docs, which automatically save. Then I copy and paste it into Substack. That might be worth a try? There are lots of apps that save as one writers, Word can if one sets it to do that. I back everything up to Google Drive. There are phone based apps one can use also. Perhaps find the one that is easiest for you to use 👍
I do the same. I use a note app if on phone and copy paste. But on laptop I always use word.
Hi Prof G.
I understand many of these issues, and the vital importance of empirical research. But it also takes quite a bit of time, and many of us pwMS don’t have years and years of time to wait for clinical trials to play out. This is not a complaint, it’s just a fact. I was Dx'd (diagnosed) with multiple sclerosis in 2002, and I was originally hopeful that science and technology in the new millennium would have concrete answers quite soo. But after
Unfortunately, Science moves very slowly. We put forward the alemtuzumab-rituximab hypothesis in 2014. If we had been funded I suspect we would have had the results by now. Saying that we can't simply adopt a treatment protocol, particularly an expensive and potentially risky one, without more evidence in the NHS. There are checks and balances in the NHS, which makes it very hard to prescribe off-label. I suspect it will be easier in the private sector.
Please note I don't do private practice.
Prof G;
I apologize, but I didn’t get to finish my post.
I was hopeful that this time in history medical science would be able to catch up to the disease, as the disease had a 167 year head start. But for the last 20+ years the people charged with developing the therapies (aka the drug companies, etc ) decided to become intransigently insular, and only come at the disease with a linear progression of similar products… as if they were catering to a MultipleSclerosis department store. We (pwMS) need more rigorous work done on figuring out how the disease works on a fundamental level, how to arrest the progression at the molecular level, and how to repair the damage if it’s possible. We don’t need more ridiculously varied alternative brands of CD 20 inhibitors, or another -imod or BTK inhibitor. It’s the waste of precious time that I’m talking about, not that the wheels of science turn slowly.
I understand about having to run clinical trials to be able to make sure that a therapy is safe and efficacious. But to be frank, we don’t have time anymore for people to fart around with science just trying to monetarily ingratiate their stockholders. I am painfully aware how cynical that sounds, but I’ve learned to be more skeptical after all that I’ve experienced in the past 20 years dealing with multiple doctors and drug companies. I was in school in 2004 and trying to transfer to a four-year university here near me. I knew a professor (Prof Peter Bryant) at the University of California Irvine for years, because my mother worked as a secretary for the dean of the pathobiology department (now known as the molecular biology department), and he was trying to help me fast track into the university. In the meantime, I was assisting in his stem cell lab at the university. At one point there was a symposium put on by the university and the then newly established CIRM (California Institute for Regenerative Medicine), and I had pretty extensive conversations with some of the scientists. I asked about being able to repair damage from multiple sclerosis with stem cells, and was told that it was a possibility someday, but that the science was still 40 to 50 years away from being able to do that, period, let alone effectively. That had a huge impact on my hopes of what was possible. I never was able to transfer to the university because the disease caught up to me exponentially, and I had to drop out of school before the disability caused so much disruption that my GPA bottomed out completely. It’s unfortunate because I really thrived in that environment.
Just a sidenote… but UCI was the home of Dr Stanley van den Noort, and I actually got a chance to meet him once before he passed away. Though he had given up his practice by then.
Quite a lot (trials / studies) going on in the MS research world - rituximab after Alemtuzumab, BTK inhibitors, Frexalimab, Sizomus, Chariot MS, Octopus, Cambridge remyelination trial…. But nothing from these trials / projects (if positive) will be available for another 5+ years. It’s like being in a desert desperate for water. A mirage appears, but as soon as you get close it moves away. Is there nothing else likely to emerge in a a shorter timeframe? What happened to the Black Swan? Why does the U.K. appear to be doing all the donkey work?
Not sure it is a mirage. When you look back at the development history of most MS treatments they take decades from concept to a licensed treatment. Sadly, this is the nature of science and drug development.
MS research has kept teams of scientists busy for decades and anti-relapse drugs have been a cash cow for pharma. Compared to research re AIDS, Covid and many cancers, MS research has been in the slow lane for too long. The case below brings tears to my eyes, but highlights the importance of breaking the current models of working which have delivered too many failures (eg anti-lingo antibody, drugs to slow / stop progression) and taken too long.
https://www.mssociety.org.uk/care-and-support/online-community/community-blog/sabrina-and-octopus-stop-ms
Some of your colleagues acknowledge that the main progress has been anti-relapse (not the real disease) drugs and the big questions have still to be answered:
https://twitter.com/SKriegerMD/status/1662612870427713536
I had my second course of Alemtuzumab last October at Royal London. Honestly, it was fine, just far, far too late; I was extremely glad to have it. So far, I haven't developed any new conditions from it, though my lymphocyte count isn't yet back to anywhere near a normal level. I'm interested in the idea of taking other treatments alongside Alumtuzumab, and would have been willing to be in a trial (and would still be willing, if I have more treatment, which I'm trying to just keep an open mind about.)
This is fascinating academic debate that never seems to mention the patients. We are the ones who have to experience/suffer/endure/be treated for these complications, often for the rest of our lives. Whilst the benefits of alemtuzumab for MS outweigh - for most of us - these risks then taking the drug isn't the issue here.
As these risks after a course of alemtuzumab treatment are well known and in many cases quite quantifiable (Graves for example) to just put them all to one side because there is insufficient Placebo Controlled, Randomised, Clinical Trial evidence at present seems to skirt past the growing body of Real World Evidence. RWE is not a fanciful notion and can be derived from observation.
>>
https://en.wikipedia.org/wiki/Real_world_evidence
<<
For example: the Whack-A-Mole trial referred to may only have had 10 participants making it woefully underpowered it is my understanding that c. 400 patients have been treated with this protocol or variations thereof. Apparently, not a single person has had any auto-immune issues related to their alemtuzumab infusion. Acknowledging that there are uncontrollable variables and this is NOT hard scientific method data it makes one wonder why there hasn't been a single incidence. In a cohort of c. 400 there would be an expectation of - taking Graves as an example - at least 1/3 having thyroid issues. Roughly, granted. But not one.
The protocol, in whatever form, was not administered by have-a-go amateurs but by specialist neurologists using drugs that have well-established safety profiles. The question of on or off-license use is a confounding factor in differing countries but should not be used to cloud the discussion about whether this expert-led attempts at 'painting outside the lines' works or not.
Until alemtuzumab regains its popularity as a go-to medicine for MS then there will be relatively little commercial interest in mitigating risks. The academic speculating discussed here has the feeling of an existential debate about the hardest science possible, not the end users.
In the meantime, there are actual people, MS patients, who are going to receive alemtuzumab who I imagine are more than willing to try something to mitigate risks. After all, they already have MS and any of the compounds discussed here are not experimental drugs.
I also understand that a lot of tweaking/playing around etc has been done by various neurologists regarding the pre and post infusion regimes of various steroids, antibiotics, and antivirals all with the aim of reducing reactions to alemtuzumab. It would be interesting to see them collated, compared, and remarked upon by an expert such as yourself.
This is actually about mitigating the long term risks to the alemtuzumab recipients using best efforts. They may not be perfect, they may not be proven beyond a shadow of doubt, they may involve using a known compound off-license (hardly a new thing for medicine when a drug for X has been observed to do Y. Think Viagra, Rogaine, Tecfidera - all eventually re-trialled but used off label initially for their effects on another condition than the initial intended indication) all in an imperfect attempt to reduce the long-term negative effects of something.
Preserving an approach in aspic has rarely been a useful approach. Innovation and discovery has often been achieved by people wishing to push boundaries. RCT is the gold standard but in the meantime the issues don't go away and there is a degree of reputable evidence. Even you had the hypothesis initially!
I agree a lot of repurposing does result from off-label use, which then sets the scene for future randomised controlled trials. One could argue that this has already happened with the alemtuzumab-rituximab whack-a-mole paper and the Australians have risen to the challenge.
It is important to note that once the alemtuzumab clinical trial programme got underway Cambridge stopped dosing off-label CAMPATH-1H for compassionate use. They had lost equipoise and they told patients that they would have to wait for the randomised trials to report out.
NHS England would potentially respond to RWE, but it will need to be in a peer-review publication and of sufficient quality for them to accept it. And possibly from multiple sources. Let's hope someone publishes it soon; a 100% success rate would make a very compelling case.
I always get wary of 100% claims. IMHO something nis never 100%. But that is the claim made. There is no further context.
You mention 400 patients have been treated with this protocol. Do you have a reference or a source? I can't find one outside the published paper.
I was told this by a very reputable source in Canada/US. Whilst I have no reason to doubt them I wouldn't bet anything significant on it because, as you say, it isn't in a paper. It seems that this is them and a colleague doing a tally and coming up with a reasonable number. I tried to phrase the fact that it is reportage carefully.
Hi Gavin, it's Elliot Frohman. Thanks for your comments as always.
I hope you are well. We missed having you at the MS Section of the AAN Chair's INTL Advisory Roundtable. Perhaps another time. You'll be very pleased to know that Tree and I are in discussion with a major benefactor concerning the funding of a randomized, prospective, controlled trial of the Teresa Frohman Whack-A-Mole protocol. Very excited about this, and agree it should be done. At one point we tried to invite you to join us, but never heard back. Best always, Elliot and Tree
Elliot, Do you have more anecdotal evidence than what you presented in your whack-a-mole paper? Some people seem to think there are now 100s of patients who have been treated with your protocol. Thanks.
Too many emails and not enough minutes or hours in a day. Apologies. Looks like the Australians have beaten you to the trial. But may be you can do one when you start rituximab earlier than 10 weeks post alemtuzumab. I would suggest W4 after the acute infection risk is waning.
Thank you for writing this - this topic interests me greatly so I’m always watching for your opinion. I wish very much I could try this process but understand the requirements of research practice. I hope the results are favourable & it’s not too late for me to benefit! :)
I'm still hung up on the palifermin behaving the opposite way they expected it to with dramatic negative consequences. Did they give these vulnerable people the first in human palifermin infusions? Yikes.
having since actually done my research (hah!) I see that it's long been used in a population where it might be hard to detect reduced thymopoesis. But still! It's weird to me to use a drug that has been used in humans on the strength of its use in nhps.
Good morning, just to add a comment on a secondary autoimmunity, in my case after HSCT. I just got a positive result for anti-NMDA-NR1-Receptor. The result was negative prior to HSCT and the bref EBV activation that had followed HSCT. Wondering if it could be a case of a secondary autoimmunity...will follow-up with doctors here.
Yes, likely. Secondary autoimmunity also occurs after AHSCT at a rate of approximately one-third of that seen with alemtuzumab.
I got a rituximab infusion at the end of my HSCT treatment - what is the role of it in this case? I am ignorant to the medicine/science in this respect. Is it a similar idea to prevent secondary autoimmunity after the chemo?